Bioactive ceramic materials are known to the art, and typically contain less than 60 mole percent SiO2, high sodium and CaO content (20-25% each), and a high molar ratio of calcium to phosphorus (ranging around five). Such materials are called xe2x80x9cbioactivexe2x80x9d because interfacial bonds form between the material and surrounding tissues. When such glasses are exposed to water or body fluids, several key reactions occur. The first is cation exchange wherein interstitial sodium and calcium ions from the glass are replaced by protons from solution, forming surface silanol groups and nonstoichiometric hydrogen-bonded complexes: 
This cation exchange also increases the hydroxyl concentration of the solution, leading to attack of the fully dense silica glass network to produce additional silanol groups and controlled interfacial dissolution:
Sixe2x80x94Oxe2x80x94Si+H+OHxe2x88x92xe2x86x92Sixe2x80x94OH+HOxe2x80x94Si
As the interfacial pH becomes more alkaline and the concentration of hydrolyzed surface silanol groups increases, the conformational dynamics attending high numbers of proximal silanol groups, combined with the absence of interstitial ions, cause these groups to repolymerize into a silica-rich surface layer:
Sixe2x80x94OH+HOxe2x80x94Sixe2x86x92Sixe2x80x94Oxe2x80x94Si+H2O
Another consequence of alkaline pH at the glass-solution interface is crystallization into a mixed hydroxyapatite phase of the CaO and P2O5 that were released into solution during the network dissolution. This takes place on the SiO2 surface. This phase contains apatite crystallites which nucleate and interact with interfacial components such as glycosaminoglycans, collagen and glycoproteins. It is thought that incorporation of organic biological constituents within the growing hydroxyapatite- and SiO2-rich layers triggers close interactions with living tissues characteristic of bioactivity. See Greenspan et al. (1994), Bioceramics 7:55-60.
Use of bioactive ceramics in implant prosthetic devices and coatings for prosthetic devices has been described, e.g. in U.S. Pat. No. 4,775,646 to Hench et al. issued Oct. 4, 1988 for xe2x80x9cFluoride-Containing Bioglass(copyright) Compositionsxe2x80x9d which teaches a glass formulation containing 46.1 mole percent SiO2, 2.6 mole percent P2O5, 26.9 mole percent CaO and 24.4 mole percent Na2O, or 52.1 mole percent SiO2, 2.6 mole percent P2O5, 23.8 mole percent CaO and 21.5 mole percent Na2O, and compositions in which 40 to 60 mole percent of the CaO is substituted with CaF2. The patent states that implants made of this material are useful where optimization of durable chemical bonding with living tissue is desirable.
Alkali-free bioactive glass compositions based on SiO2, CaO and P2O5 are disclosed in U.S. Pat. No. 5,074,916 to Hench et al. issued Dec. 24, 1991 for xe2x80x9cAlkali-Free Bioactive Sol-Gel Compositions.xe2x80x9d
Bioglass(copyright) is a registered trademark of the University of Florida licensed to USBiomaterials Corporation. Other issued patents related to this material include U.S. Pat. No. 5,486,598 issued Jan. 23, 1996 to West, et al. for xe2x80x9cSilica Mediated Synthesis of Peptides,xe2x80x9d U.S. Pat. No. 4,851,046 issued Jul. 25, 1989 to Low et al. for xe2x80x9cPeriodontal Osseous Defect Repair,xe2x80x9d U.S. Pat. No. 4,676,796 issued Jun. 30, 1987 to Merwin et al. for xe2x80x9cMiddle Ear Prosthesis,xe2x80x9d U.S. Pat. No. 4,478,904 issued Oct. 23, 1984 to Ducheyne et al. for xe2x80x9cMetal Fiber Reinforced Bioglass(copyright) Compositions,xe2x80x9d U.S. Pat. No. 4,234,972 issued Nov. 25, 1980 to Hench et al. for xe2x80x9cBioglass(copyright)-Coated Metal Substrate,xe2x80x9d and U.S. Pat. No. 4,103,002 issued Jul. 25, 1978 to Hench et al. for xe2x80x9cBioglass(copyright) Coated A1203 Ceramics.xe2x80x9d Pending applications include Patent Cooperation Treaty Publication WO 9117777 published Nov. 28, 1991, Walker, et al., inventors, for xe2x80x9cInjectable Bioactive Glass Compositions and Methods for Tissue Reconstruction,xe2x80x9d claiming a priority date of May 22, 1990 based on a U.S. application.
PerioGlas(copyright) is a registered trademark of USBiomaterials Corporation licensed to Block Drug Corporation. It refers to a synthetic bone graft particulate material containing Bioglass(copyright) ceramic. Product literature describes this material as bonding to both bone and soft tissue, and indicates it is packed directly into a bone defect. Hench, L. L. (1995) xe2x80x9cBioactive Implants,xe2x80x9d Chemistry and Industry (July 17, n. 14, pp.547-550), reports that collagen fibrils in the surrounding tissue interact directly with the surface layer which forms on bioactive glass.
PCT Publication WO 96/00536, published Jan. 11, 1996, Ducheyne et al. inventors, discloses a method of forming osseous tissue comprising filling an osseous defect with a bioceramic material.
Composite materials comprising particulate bone replacement material have been described, e.g. in U.S. Pat. No. 4,192,021 issued Mar. 11, 1980 to Deibig et al. for xe2x80x9cBone Replacement or Prosthesis Anchoring Material.xe2x80x9d This patent teaches bone replacement prosthesis anchoring materials which are mixtures of sintered calcium phosphates and biodegradable organic materials at a ratio of calcium phosphate to organic materials between 10:1 and 1:1.
U.S. Pat. No. 5,017,627, issued May 21, 1991, to Bonfield et al. for xe2x80x9cComposite Material for Use in Orthopaedicsxe2x80x9d discloses an apparently non-biodegradable polyolefin material containing particulate inorganic solid particles for bone replacement materials.
U.S. Pat. No. 5,552,454 issued Sep. 3, 1996 to Kretschmann et al. for xe2x80x9cNew Materials for Bone Replacement and for Joining Bones or Prosthesesxe2x80x9d discloses compositions comprising biodegradable waxes or polymeric resins (molecular weight 200 to 10,000) and a body-compatible ceramic material, wherein the polymer is substantially free from free carboxyl groups.
Other bioactive ceramics are disclosed in U.S. Pat. No. 4,189,325 issued Feb. 19, 1980 to Barrett et al. for xe2x80x9cGlass-Ceramic Dental Restorations,xe2x80x9d and U.S. Pat. No. 4,171,544 issued Oct. 23, 1979 to Hench et al. for xe2x80x9cBonding of Bone to Materials Presenting a High Specific Area, Porous, Silica-Rich Surface.xe2x80x9d
PCT Publication WO 96/19248 published Jun. 27, 1996 for xe2x80x9cMethod of Controlling pH in the Vicinity of Biodegradable Implants and Method of Increasing Surface Porosity,xe2x80x9d discloses the use of bioactive ceramics as pH-controlling agents in biodegradable polymeric implants.
Composite materials for bone and tissue-healing use made with biodegradable polymers having molecular weights above about 10,000 do not appear to have been disclosed in the literature, nor have the advantageous properties of these materials been reported.
All publications referred to herein are hereby incorporated by reference in their entirety.
This invention provides both porous and nonporous therapeutic implant materials comprising a biodegradable polymer and a bioactive ceramic. Such implants comprising biodegradable polymer and bioactive ceramic are termed xe2x80x9ccomposite implantsxe2x80x9d herein. Incorporation of bioactive ceramic into the polymer has a number of advantages.
An important advantage is that the material has better mechanical properties (e.g. Young""s modulus is higher) than in polymeric materials without the bioactive ceramic. Porous implant materials of this invention are preferably used as cell scaffolds, for placing in defects of cancellous (spongy, trabecular) bone. The Young""s modulus of such bone ranges from approximately 10 MPa to 3000 MPa. The porous implant material preferably has a Young""s modulus similar to that of the bone in which it is to be placed. These porous implant materials may also be used for cell scaffolds for placing in other types of bone. They may also be used as bone graft substitutes, bone on lays and for spinal fusion. Porous implant materials of this invention preferably have a Young""s modulus measured under physiological conditions (37xc2x0 C. in an aqueous environment) by the three point bending dynamic mechanical analysis described herein between about 0.1 MPa and about 100 MPa, and preferably between about 0.5 MPa and about 50 MPa, and a porosity greater than about 50%, and preferably between about 65% and about 75%, although higher porosities, e.g., up to about 90%, may also be used.
Porous implant materials of this invention may also be used for repair of soft connective tissues such as tendons, ligaments, and skin. The porous scaffold serves as a substrate for guided tissue regeneration. As the biodegradable polymer degrades, it is replaced by new healthy tissue. The surface of the bioactive ceramic component interacts with extracellular matrix components, particularly collagen type I, enhancing wound healing by providing biological surfaces for mesenchymal cell migration and by causing enhanced apposition of the tissue to the implant. By varying the type of bioactive ceramic used and its concentration within the biodegradable polymer, the biological characteristics of the implant can be tailored. Multiphase implants, e.g. as described in U.S. Pat. No. 5,607,474 issued Mar. 4, 1997 to Athanasiou et al. for xe2x80x9cMulti-Phase Bioerodible Implant/Carrier and Method of Manufacturing and Using Same,xe2x80x9d modified to contain bioactive ceramic, are also useful. For example, to attach tendon to bone, the bone phase preferably contains 45S Bioglass(copyright) ceramic, which xe2x80x9cbindsxe2x80x9d hard connective tissue such as cementum or bones, and the tendon phase preferably contains Bioglass(copyright) ceramic which interacts with both hard and soft connective tissue such as tendon or ligament. Alternatively, a single phase implant may be used, containing 55S Bioglass(copyright) ceramic, which interacts with both hard and soft tissue. In another embodiment of this invention, composite material may be used in particulate form to enhance periodontal repair where regeneration of cementum (hard tissue), periodontal ligament (soft tissue) and bone (hard tissue) is necessary. The porous nature of the implant permits the use of marrow, which contains wound healing cells, or other cells of interest.
Implant materials of this invention which are substantially non-porous (also referred to herein as xe2x80x9cfully densexe2x80x9d or xe2x80x9csolidxe2x80x9d) are preferably used for fracture fixation devices such as plates, screws and rods. The Young""s modulus of nonporous materials of this invention, tested under physiological conditions, should be between about 1 GPa and about 100 GPa when tested using the dynamic mechanical analysis three point bending test as described herein. The moduli specified herein are understood to be as so tested. For application to cancellous bone and partial weight-bearing areas of bone, the Young""s modulus is preferably between about 1 GPa and about 30 GPa. For application to full weight-bearing areas of bone, the Young""s modulus is preferably between about 5 GPa and about 30 GPa. In addition to providing increased mechanical properties to nonporous implant materials, the presence of bioactive ceramic in the material of bone fixation devices such as screws improves the ability of the implant to cut into the bone as it is drilled into place.
The bioactive ceramic (preferably Bioglass(copyright)), should be present in porous implant materials in an amount less than about 40 volume percent, and preferably less than about 30 volume percent, down to about 10 volume percent. The bioactive ceramic should be present in nonporous implant materials in an amount of about 10 volume percent to about 70 volume percent, preferably no more than about 50 to 60 volume percent.
Bioactive ceramics are known to the art as discussed above, and include, as preferred species for use in this invention, 45S, 55S, and 65S Bioglass(copyright) particles having a particle size of 90-53 xcexcm, or a particle size of 53-38 xcexcm, or alkali free sol-gel Bioglass(copyright) particles. The 65S Bioglass(copyright) product is non-active, i.e., fits under the definition of surface-passivated materials as used herein; however the sol-gel 65S Bioglass(copyright) product is surface-active. The bioactive ceramic may be used in a variety of shapes, such as irregular-shaped particles, fibers and particles having controlled geometrical shapes.
In a preferred embodiment, the bioactive ceramic is surface-passivated, as applicants have discovered, surprisingly, that under wet physiological conditions, the moduli (storage modulus and Young""s modulus) of the implant containing bioactive ceramic decrease compared to the moduli measured under dry conditions. This problem is solved by passivating the surface of the bioactive ceramic (making it non-reactive to water). The term xe2x80x9csurface-passivatedxe2x80x9d herein thus means that the surface of the bioactive ceramic in the polymeric composite material has been made incapable of reacting with water, preferably by pre-reacting with water to form an apatitic layer. Alternatively, the bioactive ceramic particles may be coated with a polymeric film, as by dispersing them in a weak solution of polymer and drying, before incorporation into the polymer. This alters the surface of the bioactive ceramic to allow better bonding of the polymer but does not prevent further bioactivity of particle surfaces exposed to the aqueous environment when implanted. For example, pre-reacting forms a slight apatite layer which will interfacially bond with the polymer phase, but in a prepared implant, the surface of the bioactive ceramic exposed to the body still reacts to form the interfacial bond.
In an alternative embodiment of this invention, a silane coupling agent is used to coat the bioactive ceramic for inclusion in the composite material to passivate the surface of the bioactive material and strengthen the interface between the polymer and the bioactive ceramic. An amount of such coupling agent sufficient to coat the surface of the particles used is an effective amount.
Bioactive ceramic materials which are not surface-passivated and which do react with water are called xe2x80x9csurface-activexe2x80x9d materials herein. In one embodiment of this invention, both surface-active and surface-passivated materials are incorporated into the biodegradable polymeric material. Since these two types of bioactive ceramic have different effects on mechanical properties, the ratio of surface-active to surface-passivated material may be varied to achieve desired mechanical properties in the finished implant material while maintaining a desired total bioactive ceramic content.
Composite therapeutic implant materials of this invention comprising surface-passivated bioactive ceramic have enhanced (greater) mechanical properties both when compared to such compositions containing non-surface-passivated bioactive ceramics and to such compositions containing no bioactive ceramics. Mechanical properties are described herein in terms of Young""s modulus and storage modulus. Young""s modulus may be measured by means known to the art. With respect to the studies of materials of this invention reported herein, Young""s modulus has been found to be about an order of magnitude less than storage modulus.
Composite materials of biodegradable polymers and bioactive ceramics are also effective to buffer the pH of the environment of an implant made with the material as the implant degrades so as to avoid potentially deleterious effects of acidic degradation products.
The applicants have also discovered that the addition of bioactive ceramic particles in making porous biodegradable polymers decreases the molecular weight and glass transition temperature of the implant, which can influence the degradation time of the implant. Accordingly, methods of making porous biodegradable polymeric implant materials comprising bioactive ceramics are provided which take into account these effects and allow selection of appropriate starting materials with appropriate molecular weights to provide finished implants of selected molecular weights, degradation times, storage moduli, or Young""s moduli and glass transition temperatures. In porous implant materials, addition of bioactive ceramic decreases the molecular weight of the material about 1 percent per percent of bioactive ceramic added.
Methods of using the materials of this invention for accelerated healing of defects in bone and other tissue are also provided.
Biodegradable polymeric cylinders, wafers, spheres, strips, films, and irregularly-shaped implants, as well as particulate bone-graft materials containing bioactive ceramics are provided herein, as are biodegradable polymeric hand-shapable materials containing bioactive ceramics and biodegradable polymeric materials capable of continuous, smooth release of bioactive agents and containing bioactive ceramics.
The term xe2x80x9cbiodegradablexe2x80x9d means capable of breaking down over time inside a patient""s body or when used with cells to grow tissue outside of the body. A therapeutic implant is a device used for placement in a tissue defect in a patient (human or animal) to encourage ingrowth of tissue and healing of the defect. Composite implants of this invention may comprise cells.
Polymers known to the art for producing biodegradable implant materials may be used in this invention. Examples of such polymers are polyglycolide (PGA), copolymers of glycolide such as glycolide/L-lactide copolymers (PGA/PLLA), glycolide/trimethylene carbonate copolymers (PGA/TMC); polylactides (PLA), stereocopolymers of PLA such as poly-L-lactide (PLLA), Poly-DL-lactide (PDLLA), L-lactide/DL-lactide copolymers; copolymers of PLA such as lactide/tetramethylglycolide copolymers, lactide/trimethylene carbonate copolymers, lactide/xcex4-valerolactone copolymers, lactide xcex5-caprolactone copolymers, polydepsipeptides, PLA/polyethylene oxide copolymers, unsymmetrically 3,6-substituted poly-1,4-dioxane-2,5-diones; poly-xcex2-hydroxybutyrate (PHBA), PHBA/xcex2-hydroxyvalerate copolymers (PHBA/HVA), poly-xcex2-hydroxypropionate (PHPA), poly-p-dioxanone (PDS), poly-xcex4-valerolatone, poly-xcex5-caprolactone, methylmethacrylate-N-vinyl pyrrolidone copolymers, polyesteramides, polyesters of oxalic acid, polydihydropyrans, polyalkyl-2-cyanoacrylates, polyurethanes (PU), polyvinyl alcohol (PVA), polypeptides, poly-xcex2-maleic acid (PMLA), and poly-xcex2-alkanoic acids.
Preferred biodegradable polymers for use in making the materials of this invention are known to the art, including aliphatic polyesters, preferably polymers of polylactic acid (PLA), polyglycolic acid (PGA) and mixtures and copolymers thereof, more preferably 50:50 to 85:15 copolymers of D,L-PLA/PGA, most preferably 55/45 to 75:25 D,L-PLA/PGA copolymers. Single enantiomers of PLA may also be used, preferably L-PLA, either alone or in combination with PGA.
Preferably the polymeric implant material has a molecular weight between about 25,000 and about 1,000,000 Daltons, more preferably between about 40,000 and about 400,000 Daltons, and most preferably between about 55,000 and about 200,000 Daltons.
Also provided is a biodegradable film for application to a wound in a patient comprising a biodegradable polymer and between about 10 and about 70 percent of a bioactive ceramic. This invention also teaches methods of making porous composite therapeutic implant materials comprising bioactive ceramic and biodegradable polymer comprising preparing said polymer in uncured form, mixing a bioactive ceramic into said polymer, placing said mixture into a mold and curing under vacuum pressure conditions to produce the porous composite implant material.
Methods of making substantially nonporous composite therapeutic implant materials are also taught, comprising preparing said polymer in uncured form, mixing a bioactive ceramic into said polymer, and curing said mixture under conditions of heat and pressure to produce a substantially nonporous composite implant material.
The composite implant materials of this invention may be used by forming said materials into implant devices selected from the group consisting of: tissue scaffolds with and without cells, granular bone graft substitute material, two-phase osteochondral implants, weight-bearing bone implants, no- to low-weight-bearing implants or fixation devices, tacks, pins, screws, bone on lays, and films.
Preferably the polymeric implant material is capable of maintaining a pH between about 6 and about 9 in a physiological environment, and more preferably between about 6.5 and about 8.5.